A method for generating a stable dispersion of nucleating ice crystals having a size for inducing nucleation during freeze drying. The ice crystals are formed using a cryogenic fluid and a carrier gas saturated with vapor such as water vapor. A sequential injection method is used to facilitate the growth of larger ice crystals for improved nucleating performance during freeze drying.
Intervial variability in freezing can be a significant scale-up problem in pharmaceutical freeze drying because a freezing procedure optimized in the laboratory may not transfer exactly to a manufacturing scale where the air is virtually free of particulate impurities. This variability results because of supercooling of water in very clean environments which can cause the water to remain as a liquid, even at temperatures as low as −40° C. A vial filled with aqueous product being cooled in such a particulate-free atmosphere can therefore freeze anywhere between about 0° C. and −40° C.
A typical pharmaceutical freeze drying system involves the freezing and subsequent freeze drying of hundreds to thousands of small vials containing the typically aqueous based product to be processed. Due to the extremely clean production environments, all or most of the vials could undergo supercooling and each freeze at different temperatures below 0° C. Vials freezing at higher temperatures have preferred ice structure and shorter primary drying time compared to vials freezing at lower temperatures. Optimizing cycle time is therefore very difficult because there is difficulty in controlling or eliminating the uncertainty in vial-to-vial freezing temperatures and the subsequent lack of common drying behavior.
One way to reduce supercooling and/or cause all supercooled vials to freeze at the same time is to induce freezing by introducing ice nuclei into the supercooled solution. The presence of the ice nuclei provides a suitable and benign substrate for the supercooled water to crystallize onto and freeze into ice. If all vials are cooled to the same temperature are subjected to such a freezing substrate at approximately the same time, then all the vials will freeze at that time. This in turn will eliminate the vial-to-vial variability resulting from vials freezing at different degrees of supercooling and leads to improved product and process control.
Stability and size of ice nuclei are considered critical factors in inducing freezing in vials for two reasons. First, the ice nuclei formed must remain in the solid state and not dissipate, sublimate or melt before they can make their way into the vials and into the solution therein. Second, the nuclei must overcome and penetrate the surface region of the solution inside the vial and cause the necessary perturbation to induce freezing of the supercooled solution. Larger ice nucleating particles are preferred so that they actually perturb the solution to cause the structural orientation necessary for crystallization or act as a substrate for the supercooled solution to freeze on, as opposed to remaining suspended above the solution surface.
Generating ice crystals of preferred size requires an understanding of the microphysics involved. In nature, snow crystals form when supercooled water droplets freeze on suspended dust particles which serve as freezing nuclei. Once an ice crystal is formed, its growth or decay will depend on the humidity conditions around it. The driving force for ice crystal growth is supersaturation which is a function of ice temperature.
Since the saturated water vapor pressure of ice is lower than that of supercooled water at the same temperature, the water vapor can become supersaturated with respect to ice, causing the crystals to grow at the expense of other water droplets via vapor deposition (the Bergeron process). Crystals can also grow by collision with supercooled water droplets which subsequently freeze. Depending on the degree of supersaturation and temperature, crystals of different size and geometries can evolve and this has been supported by several studies, such as “The Physics of Snow Crystals”, Kenneth G. Libbrecht, 2005 Rep. Prog. Phys. 68; “Microphysics of Clouds and Precipitation”, Chapter 2, Volume 17, 2006 Springer. If this driving force is not sufficiently high, the ice crystals can sublimate into vapor or melt into liquid water before reaching a critical size.